The growing threats of nuclear warfare and terrorism highlight the need to develop effective and non-toxic radiation countermeasures that can increase survival of ARS victims and alleviate post-irradiation thrombocytopenia when administered at least 12-24 hours after a nuclear event. CBLB502, a novel recombinant protein derived from Salmonella FliC flagellin, is a powerful anti- radiation drug that fits those requirements. CBLB502 strongly reduces the duration and severity of radiation-induced thrombocytopenia in non-human primates and reduces mortality of mice and non-human primates even if injected 16-48 hours after lethal irradiation. Multiple cytokines are induced by CBLB502, possibly contributing to its anti-radiation and anti-thrombocytopenia activities. CBLB502 displays low toxicity (with therapeutic doses >100 times lower than NOAEL in mice) and reduced immunogenicity. The goals of the current proposal are investigating the mechanism underlying the anti-thrombocytopenia activity of CBLB502 and optimization of mitigation regimens aimed at rescuing primates >12 hours after exposure to lethal irradiation. We will (1) test the direct influence of CBLB502 administration on megakaryocyte progenitors in vitro; (2) evaluate the effect of CBLB502, with and without radiation, on mouse thrombopoiesis in vivo, and (3) optimize anti-thrombocytopenia and life rescuing CBLB502 treatment given >16 hours after highly lethal (LD70) irradiation in non-human primates. The growing threats of nuclear warfare and terrorism highlight the need to develop effective and non-toxic radiation countermeasures that can increase survival of ARS victims and alleviate post-irradiation thrombocytopenia when administered at least 12-24 hours after a nuclear event. CBLB502 a novel recombinant protein anti-radiation drug candidate, strongly reduces the duration and severity of radiation-induced thrombocytopenia in non-human primates and reduces mortality of mice and non-human primates even if injected 16-48 hours after lethal irradiation exposure. The goals of the current proposal are investigating the mechanism underlying the anti-thrombocytopenia activity of CBLB502 and optimization of mitigation regimens aimed at rescuing primates >12 hours after exposure to lethal irradiation. [unreadable] [unreadable] [unreadable]